The long-term goal of this research project is to define genetic and metabolic factors involved in the development of atherosclerosis. This disease is the leading cause of mortality in the Western world and its risk of onset appears to be influenced by nutritional and genetic factors. The hereditary component in atherosclerosis is likely to be complex and characterized by the involvement of a large number of genes, many of which participate in determining the levels and structures of plasma lipoproteins. The study described here will focus on genetic factors controlling high density lipoproteins (HDL) and the role of HDL in atherosclerosis. This interest stems from human epidemiological studies which show a strong association of high plasma concentrations of HDL with a reduced risk of heart disease. The mechanism of protection and why individual differences exist in plasma levels of HDL subclasses is not known. The mouse genetic system is used here to determine the genetic and physiological factors giving rise to these differences and to shed light on the manner in which HDL protect against heart disease. The mouse is the classical mammal for genetic studies because of the hundreds of inbred strains, detailed chromosome map, special genetic tools and unusual strains. In contrast, only limited aspects of the genetic regulation of lipoproteins can be examined directly in humans. Important complications in human studies are interactions between environment and genetic factors, and genetic heterogeneity among human populations which makes it difficult to study the effects of individual genes unless those effects are relatively gross. Polymorphisms have been identified among mouse strains using antibodies and cDNA clones to specific proteins involved in lipid transport (LCAT, lipases, transfer proteins, apolipoproteins, etc.). These polymorphisms will be used to investigate genetic and physiological factors giving rise to different HDL subpopulations. Further, a gene determining atherosclerosis susceptibility in mice, called Ath-1, will be characterized. Its action involves metabolic mechanisms related to changes in plasma HDL levels. The identity of Ath-1, in terms of its gene product, will be characterized. Its action involves metabolic mechanisms related to changes in plasma HDL levels. The identity of Ath-1, in terms of its gene product, will be determined using antibodies and cDNA clones specific for lipid transport proteins. Together, this information will shed light on basic factors controlling lipid transport and atherosclerosis.